Total synthesis of potent antitumor agent (-)-lasonolide A: a cycloaddition-based strategy.

Chemistry, an Asian Journal
Arun K Ghosh, Gangli Gong

Abstract

A detailed account of the enantioselective total synthesis of (-)-lasonolide A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an alpha-alkoxyacetimide derivative containing an alpha' stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero-Diels-Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively.

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Citations

Feb 14, 2012·The Journal of Organic Chemistry·Arun K Ghosh, Guo-Bao Ren
Aug 21, 2009·The Journal of Pharmacology and Experimental Therapeutics·Richard A IsbruckerAmy E Wright
Nov 20, 2012·Cell Cycle·Yong-Wei ZhangYves Pommier
Aug 23, 2016·Journal of the American Chemical Society·Barry M TrostRainer Kalkofen
Dec 7, 2013·Journal of the American Chemical Society·Barry M TrostDaniel R Fandrick
Apr 20, 2014·Organic & Biomolecular Chemistry·Nadiah Mad NasirPaul A Clarke

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